1. Field of the Invention
This invention concerns methods, agents and kits for diagnosis, detection and prediction of preterm labor or initiation of term labor during pregnancy. In particular, the invention concerns detection of levels of nitric oxide in pregnant myometrium using non-invasive non-surgical or surgical methods for detection of nitric oxide in blood, plasma, serum, urine, saliva, bioptic or other tissue samples. Additionally, this invention concerns a non-invasive and nonsurgical diagnostic procedures and kits for detecting preterm labor or initiation of labor.
2. Background and Related Disclosures
Spontaneous preterm labor and/or detection of beginning of term labor at home during pregnancy remains an increasing problem confronting the medical community.
Preterm labor, whether occurring spontaneously or the one which invariably follows any significant transuterine fetal manipulation such as needle puncture, fetoscopy, or hysterotomy for fetal surgery, presents a serious problem and is a limiting factor for all types of fetal intervention. The severe forms of spontaneous preterm labor or labor induced by an incision in the gravid uterus for open fetal surgery is resistant to all known forms of tocolysis. The management of preterm labor after fetal surgery is particularly difficult and dangerous for mother and fetus because aggressive treatment with therapeutics, such as magnesium sulfate, betamimetics and other hemodynamically-active tocolytic agents has resulted in sequelae for both mother and fetus.
Once preterm labor is diagnosed, the risks and benefits of labor inhibition must be weighed against those of allowing delivery to occur. For these reasons, the early diagnosis of preterm labor is very important.
Patients undergoing hysterotomy and fetal surgery typically experience difficulty with preterm labor despite treatments involving a regimen of preoperative indomethacin, intraoperative deep halogenated inhalation anesthesia, and postoperative administration of indocin, magnesium sulfate, and betamimetics. The majority of these patients has visible and palpable intraoperative uterine contractions often associated with fetal bradycardia from cord compression. These intraoperative contractions respond erratically to deepening anesthesia and to acute administration of magnesium sulfate or terbutaline. All the patients experience significant labor postoperatively. In mild form, such labor can be controlled by administration of intravenous tocolytics for few days. In severe form, it takes a week or longer to control post-operative labor with intravenous medication before oral or subcutaneous pump medication can be used. All patients undergoing hysterotomy eventually develop uncontrolled preterm labor, premature rupture of membranes, and premature delivery from 27-34 weeks gestation.
It would be therefore highly advantageous to provide non-surgical or non-invasive methods for early detection, diagnosis and prediction of preterm labor.
Similarly, the definite diagnosis of the beginning of the full term labor is problematic. Often, the mother either misinterprets the symptoms as the beginning of labor and is rushed to a doctor or hospital too early or misinterprets the symptoms other way around and neglects to go to the hospital on time often resulting in delivery outside of the hospital, in ambulances, etc., where the hygienic and medical care conditions for the infant and mother are less than optimal.
Thus, it would be also to the advantage of the pregnant woman to have available an easy home test for detection of imminent labor beginning.
Nitric oxide (NO) is a free radical with a very short half-life. Nitric oxide is synthesized from the amino acid L-arginine by the nitric oxide synthase (NOS). So far, the only clearly established role for nitric oxide is as a cytotoxic molecule for invading microorganisms and tumor cells. However, other physiological activity, such as acting as a neurotransmitter in the brain and in the periphery, affecting gastrointestinal tract motility and penile erection were also observed. Nitric oxide is produced in vascular endothelial cells by the nitric oxide synthase and seems to mediate vascular smooth muscle relaxation by increasing levels of cGMP. Its effect on relaxation of intrapulmonary artery and vein was described in J. Pharmacol. Exp. Ther., 228:33-42 (1984).
Nitric oxide, its physiology, pathophysiology and pharmacology is described in Pharmacological Reviews, 43:109-134 (1991). While there were some in vitro studies described in Brit. J. Pharmacol., 34:604-612 (1968) concerning the effect of nitric oxide precursors on animal isolated uterus, such studies did not lead to any conclusion or advancement useful for control of labor, particularly preterm labor in human or mammal pregnancy. Two prior patents by inventors, namely, U.S. Pat. No. 5,508,045 issued on Apr. 16, 1998 and U.S. Pat. No. 5,830,848 issued on Nov. 3, 1998, address aspects of usefulness of NO on preterm labor. These patents are hereby incorporated by reference.
The current invention provides non-surgical non-invasive or surgical methods suitable for detection, diagnosis and prediction of preterm labor, which enable clinicians to control, manipulate or inhibit preterm labor or for detection of beginning of a term labor. The methods can also be used for detection of nitric oxide synthase in surgically obtained bioptic tissue samples. The methods give a clinician and/or a pregnant woman fair warning for the imminent risk of preterm labor or timely forewarning of the impeding term labor until now unavailable. Such diagnosis, detection or prediction of preterm or term labor have not been heretofore available.
Finally, the methods provide a non-invasive diagnostic tools and kits for detecting the presence or impending onset of premature labor by monitoring levels and decreased production of inducible nitric oxide synthase expression.
All patents and publications cited herein are hereby incorporated by reference in their entirety.